Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex
Background: A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responde...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Biological Psychiatry Global Open Science |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667174322000027 |
| _version_ | 1797948282561888256 |
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| author | Yuki Funayama Haiyan Li Erina Ishimori Ayako Kawatake-Kuno Hiromichi Inaba Hirotaka Yamagata Tomoe Seki Shin Nakagawa Yoshifumi Watanabe Toshiya Murai Naoya Oishi Shusaku Uchida |
| author_facet | Yuki Funayama Haiyan Li Erina Ishimori Ayako Kawatake-Kuno Hiromichi Inaba Hirotaka Yamagata Tomoe Seki Shin Nakagawa Yoshifumi Watanabe Toshiya Murai Naoya Oishi Shusaku Uchida |
| author_sort | Yuki Funayama |
| collection | DOAJ |
| description | Background: A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies. Methods: We used the large variance in behavioral responses to long-term treatment with multiple classes of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and used virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety-like behaviors. Results: Cartpt expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non–monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic (gamma-aminobutyric acidergic) neurons of the anterior cingulate cortex led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background. Conclusions: These data demonstrate that activation of CART peptide signaling in GABAergic neurons of the anterior cingulate cortex is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience. |
| first_indexed | 2024-04-10T21:40:52Z |
| format | Article |
| id | doaj.art-ec12633b3b604b35b325b430ddb60b1b |
| institution | Directory Open Access Journal |
| issn | 2667-1743 |
| language | English |
| last_indexed | 2024-04-10T21:40:52Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biological Psychiatry Global Open Science |
| spelling | doaj.art-ec12633b3b604b35b325b430ddb60b1b2023-01-19T04:17:59ZengElsevierBiological Psychiatry Global Open Science2667-17432023-01-01318798Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate CortexYuki Funayama0Haiyan Li1Erina Ishimori2Ayako Kawatake-Kuno3Hiromichi Inaba4Hirotaka Yamagata5Tomoe Seki6Shin Nakagawa7Yoshifumi Watanabe8Toshiya Murai9Naoya Oishi10Shusaku Uchida11SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, Kyoto, JapanSK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, Kyoto, JapanSK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, JapanSK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, JapanSK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, JapanDivision of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, JapanDivision of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, JapanDivision of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, JapanDivision of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, JapanSK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, Kyoto, JapanSK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; Naoya Oishi, M.D., Ph.D.SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; Address correspondence to Shusaku Uchida, Ph.D.Background: A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies. Methods: We used the large variance in behavioral responses to long-term treatment with multiple classes of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and used virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety-like behaviors. Results: Cartpt expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non–monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic (gamma-aminobutyric acidergic) neurons of the anterior cingulate cortex led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background. Conclusions: These data demonstrate that activation of CART peptide signaling in GABAergic neurons of the anterior cingulate cortex is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience.http://www.sciencedirect.com/science/article/pii/S2667174322000027Anterior cingulate cortexAntidepressant responseDepressionGABAergic neuronsStress resilienceTranscriptome |
| spellingShingle | Yuki Funayama Haiyan Li Erina Ishimori Ayako Kawatake-Kuno Hiromichi Inaba Hirotaka Yamagata Tomoe Seki Shin Nakagawa Yoshifumi Watanabe Toshiya Murai Naoya Oishi Shusaku Uchida Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex Biological Psychiatry Global Open Science Anterior cingulate cortex Antidepressant response Depression GABAergic neurons Stress resilience Transcriptome |
| title | Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex |
| title_full | Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex |
| title_fullStr | Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex |
| title_full_unstemmed | Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex |
| title_short | Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex |
| title_sort | antidepressant response and stress resilience are promoted by cart peptides in gabaergic neurons of the anterior cingulate cortex |
| topic | Anterior cingulate cortex Antidepressant response Depression GABAergic neurons Stress resilience Transcriptome |
| url | http://www.sciencedirect.com/science/article/pii/S2667174322000027 |
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